This application addresses the Challenge Area (15) Translational Science and specific high priority Challenge Topic 15-CA-102* Understanding mechanisms of hormone refractory cancers for therapeutic targeting. Androgens, the Androgen Receptor (AR) and the AR-signaling pathway are intimately associated with prostate carcinogenesis. Suppressing AR-mediated signaling currently represents the most effective approach for treating metastatic disease. However, despite substantial clinical responses, androgen deprivation therapy (ADT) for metastatic prostate cancer rarely results in durable remissions or cures. Most cancers progress to a clinical state synonymously termed Stage D3, androgen-independent, or hormone-refractory. However, substantial clinical and laboratory data indicate that these latter terms are actually misnomers. Recognizing that the mechanisms underlying cancer progression are complex, for clarity and simplicity this clinical state is more accurately classified as Castration Resistant Prostate Cancer (CRPC). This term allows for inclusion of known and hypothesized processes that allow for prostate cancer growth in an androgen-depleted environment. The molecular events leading to CPRC remain an active area of investigation and represent a focal point for therapies designed to reduce the morbidity and mortality attributed to prostate cancer. A key starting point for these studies centers on the observation that the vast majority (but not all) of CRPC continue to exhibit robust androgen-regulated cellular processes (e.g. PSA synthesis/secretion), indicating that AR signaling is maintained or reconstituted. This finding has prompted a search for mechanisms that contribute to continued AR activation in the castrate environment. While the current focus appropriately centers on AR and the ARpathway as the focal point for understanding and treating CRPC, it is important for the field to anticipate therapy- resistance mechanisms that will be operative once interventions have effectively ablated AR signaling. Our preliminary studies involving a spectrum of CRPC metastases have demonstrated that significant heterogeneity exists in the level of AR action: some CRPC tumors exhibit robust AR signaling equal to that of localized, hormone na[unreadable]ve prostate cancers and others have trivial or no AR activity (effectively "AR-null"). Importantly, even in patients with tumors that demonstrate persistent AR signaling, there are infrequent tumor deposits with no or limited AR activity. The data we have assembled over the past several years supports the segregation of CRPC into two broad phenotypic categories---each with multiple subtypes---initially defined with respect to amplitude of AR signaling: tumors with preserved AR activity (AR-ON) and those with diminished or no AR activity (AR-OFF). While individuals are likely to have disease in which one phenotype predominates over the other, most patients will have some tumors exhibiting both phenotypes. We anticipate that significant improvements in prostate cancer outcomes will result from identifying the key molecular pathways associated with each CRPC phenotype (AR-ON v AR-OFF) and coordinately targeting those distinct pathways responsible for continued cell survival in men with CRPC. At this time, it is unclear what phenotypes, genotypes, and attendant dominant growth and survival pathways will be operative in either AR-ON or AR-OFF CRPC. The goal of this research proposal is to define, categorize, and target, the dominant cellular pathways that allow for prostate cancer survival/proliferation in AR-ON and AR-OFF CRPC. To accomplish this goal, two Specific Aims are proposed: Aim 1 will integrate genome-scale bioinformatics-based approaches with quantitative measurements of gene expression measurements to define the pathways associated with AR-on and AR-off states of CRPC;Aim 2 will determine if targeting/inhibiting the pathway(s) associated with AR-on and AR-off CRPC will restrain castration resistant tumor growth. A key attribute of this research proposal centers on the direct evaluation of human biospecimens for the evaluation of CRPC diversity. To efficiently carry out our objectives, we have assembled experts from 3 academic centers with extensive basic science and clinical research programs devoted to the study of advanced prostate cancer. These centers have long traditions of excellence in prostate cancer care and research and have contributed broadly to their local economies and in discoveries that have created economic growth. The current proposal would positively impact the economy by creating or retaining 5 jobs in Seattle and Durham and their collaborating institutions. (According to the Biomedical Industry, for every one employee of a biomedical organization, another three to five will be employed in firms that service that industry.) We are seeking this Challenge Grant to rapidly implement our research strategy with the goal of developing novel stratification biomarkers capable of directing specific therapies to those patients most likely to derive benefit. All research findings and data will be made available to the research community through a freely-accessible project-specific website. PUBLIC HEALTH RELEVANCE: Advanced, metastatic prostate cancer that progresses following hormone (androgen) suppression, has no known cure, and contributes to substantial morbidity and mortality. This proposal aims to categorize advanced castration-resistant prostate cancers into discrete molecular subtypes using comprehensive measures of gene expression, and define those biochemical pathways that contribute to continued tumor survival and growth. The relevance of molecularly-defined survival pathways will be assessed in preclinical models, and promising targets will be advanced and prioritized for the development of human clinical trials. The project will generate new concepts and provide new jobs with training in advanced biomedical research including bioinformatics. The project also has the potential for further economic development by identifying new therapies for prostate cancer that will require advancement through the pharmaceutical industry.